In vitro: In AML cells, SP2509 inhibits the association of LSD1 with CoREST, increases promoter-specific H3K4Me3 and induces p53, p21 and C/EBPα. SP2509 also significantly inhibits the colony growth and induces apoptosis of OCI-AML3. In addition, SP2509 induces differentiation of cultured and primary AML cells, and exerts synergistic lethal activity when used in combination with panobinostat.
In vivo: In mice bearing OCI-AML3 xenografts, SP2509 (25 mg/kg i.p.) significantly improved the survival of the mice, while co-treatment with SP2509 and panobinostat exerts superior in vivo activity.
|Cell lines||OCI-AML3, MV4-11 and MOLM13 cells|
|Preparation method||Cultured AML cells are treated with SP2509 and/or PS for 96 h. At the end of treatment, cells are washed free of the drugs and 500 cells per condition are plated in methylcellulose and incubated at 37 °C. Colony formation is measured 7–10 days after plating.|
|Incubation time||96 h|
|Animal models||NOD/SCID mice bearing OCI-AML3 xenografts|
|Formulation||20% Cremaphor, 20% DMSO, 60% sterile water|
|Dosages||25 mg/kg twice per week|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||38 mg/mL in DMSO|
Stepwise assembly of functional C-terminal REST/NRSF transcriptional repressor complexes as a drug target.
Inui K, et al. Protein Sci. 2017 May;26(5):997-1011. PMID: 28218430.
Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.
Fiskus W, et al. Leukemia. 2014 Nov;28(11):2155-64. PMID: 24699304.
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